Structure‐Based Drug Design for G Protein‐Coupled Receptors

Congreve, Miles; Christopher, John; Graaf, Chris de

doi:10.1002/0471266949.bmc269

Cited by 3 publications

(3 citation statements)

References 254 publications

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“…The same binding mode was also described in recent works. 18,25,31,59 Departing from the binding site. As illustrated in Figure 2 and S1, the first movement from the binding state (Figure S1.A) is a rotation of the charged end of the molecule.…”

Section: Resultsmentioning

confidence: 99%

Investigating the Unbinding of Muscarinic Antagonists from the Muscarinic 3 Receptor

Jorro

Gehrke

Badaoui

et al. 2023

Preprint

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Patient symptom relief is often heavily influenced by the residence time of the inhibitor-target complex. For the human muscarinic receptor 3 (hMR3), tiotropium is a long-acting bronchodylator used in conditions such as asthma or chronic obstructive pulmonary disease (COPD). The mechanistic insights of this inhibitor remain unclear, specifically, elucidation of the main factors determining the unbinding rates could help develop the next generation of antimuscarinic agents. Using our novel unbinding algorithm, we were able to investigate ligand dissociation from hMR3. The unbinding paths of tiotropium and two of its analogues, N-methylscopolamin and homatropine methylbromide show a consistent qualitative mechanism and allowed us to identify the structural bottleneck of the process. Furthermore, our machine learning-based analysis identified key roles of the ECL2/TM5 junction involved at the transition state. Additionally, our results point at relevant changes at the intracellular end of the TM6 helix leading to the ICL3 kinase domain, highlighting the closest residue L482. This residue is located right between two main protein binding sites involved in signal transduction for hMR3s activation and regulation. We also highlight key pharmacophores of tiotropium that play determining roles in the unbinding kinetics and could aid towards drug design and lead optimization.

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Section: Resultsmentioning

confidence: 99%

Investigating the Unbinding of Muscarinic Antagonists from the Muscarinic 3 Receptor

Jorro

Gehrke

Badaoui

et al. 2023

Preprint

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“…Over the last three decades, protein crystallography and structure-based drug design (SBDD) have become gold standards across the pharmaceutical industry for the identification of ligand binding pockets and the optimization of drug candidates for clinical development. While SBDD has proven successful for many important targets, including G protein-coupled receptors (GPCRs), 16 its applicability to several membrane protein targets, such as Na V channels, has been limited due to the extreme difficulties with their iterative crystallization and structure determination. 13 Cryogenic electron microscopy (cryo-EM) has recently emerged as a transformative technique to determine the high-resolution structures of diverse protein targets and has proven particularly effective for membrane proteins that are recalcitrant to crystallization.…”

Section: Introductionmentioning

confidence: 99%

CryoEM reveals unprecedented binding site for Na_V1.7 inhibitors enabling rational design of potent hybrid inhibitors

Kschonsak

Jao

Arthur

et al. 2022

Preprint

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The voltage-gated sodium (NaV) channel NaV1.7 has been identified as a potential novel pain target due to its striking human genetics. However, clinically available drugs (e.g. lidocaine, carbamazepine, etc.) are not selective among the nine NaV channel subtypes, NaV1.1-NaV1.9, and the two currently known classes of NaV1.7 subtype-selective inhibitors (aryl- and acylsulfonamides) have undesirable characteristics that may limit their development. Moreover, understanding of the structure-activity relationships of the acylsulfonamide class of NaV1.7 inhibitors, exemplified by the clinical development candidate GDC-0310, has been based solely on a single co-crystal structure of an arylsulfonamide inhibitor series. To advance inhibitor design targeting the NaV1.7 channel, we established an iterative system to routinely obtain high-resolution ligand bound NaV1.7 structures using cryogenic electron microscopy (cryo-EM). We report that GDC-0310 engages the NaV1.7 voltage-sensing domain 4 (VSD4) through an unexpected binding mode orthogonal to the arylsulfonamide class binding pose, which identifies a previously unknown ligand binding site in NaV channels. This finding enabled the design of a novel hybrid inhibitor series that bridges the aryl and acylsulfonamide binding pockets and allows for the generation of molecules with substantially differentiated structures and properties. Overall, this study highlights the power of cryo-EM methods to pursue challenging drug targets using iterative and high-resolution structure-guided inhibitor design. It also underscores an important role of the membrane bilayer in the discovery of selective NaV channel modulators.

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“…3b) that acts as an allosteric modulator [12] and should be taken into account in molecular docking to GPCRs [13]. Inactive states of GPCRs are adapted for drug design or virtual screening of antagonists/inverse agonists, whereas active states should be adapted for drug design of agonists [14,15]. Design of biased agonists (agonists specific of a signaling pathway) raises an additional level of complexity [16].…”

Section: Introductionmentioning

confidence: 99%

Homology Modeling of Class A G-Protein-Coupled Receptors in the Age of the Structure Boom

Tiss¹,

Boubaker²,

Henrion³

et al. 2021

Methods in Molecular Biology

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With 700 members, G protein-coupled receptors of the rhodopsin family (class A) form the largest membrane receptor family in humans and are the target of about 30% of presently available pharmaceutical drugs. The recent boom in resolved structures of GPCRs led to the structural resolution of 57 unique receptors in different states (39 receptors in inactive state only, 2 receptors in active state only and 16 receptors in different activation states). In spite of these tremendous advances, most computational studies on GPCRs, including molecular dynamics simulations, virtual screening and drug design, rely on GPCR models obtained by homology modeling. In this article, we detail the different steps of homology modeling with the MODELLER software, from template selection to model evaluation. The present structural boom provides closely related templates for most receptors, except for the LGR (Leucine-rich repeat) and MRG (Mas-related) receptors. If, in these templates, some of the loops are not resolved, the numerous available structures give the opportunity to find loop templates with similar length for equivalent loops. However, simultaneously, the large number of putative templates leads to model ambiguities that may require additional information based on multiple sequence alignments or molecular dynamics simulations to be resolved. Using the modeling of the human bradykinin receptor B1 as a case study, we show how several templates are managed by MODELLER, and how the choice of template(s) and of template fragments can improve the quality of the models. We also give examples of how additional information and tools help the user to resolve ambiguities in GPCR modeling.

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Structure‐Based Drug Design for G Protein‐Coupled Receptors

Cited by 3 publications

References 254 publications

Investigating the Unbinding of Muscarinic Antagonists from the Muscarinic 3 Receptor

Investigating the Unbinding of Muscarinic Antagonists from the Muscarinic 3 Receptor

CryoEM reveals unprecedented binding site for Na_V1.7 inhibitors enabling rational design of potent hybrid inhibitors

Homology Modeling of Class A G-Protein-Coupled Receptors in the Age of the Structure Boom

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Structure‐Based Drug Design for G Protein‐Coupled Receptors

Cited by 3 publications

References 254 publications

Investigating the Unbinding of Muscarinic Antagonists from the Muscarinic 3 Receptor

Investigating the Unbinding of Muscarinic Antagonists from the Muscarinic 3 Receptor

CryoEM reveals unprecedented binding site for NaV1.7 inhibitors enabling rational design of potent hybrid inhibitors

Homology Modeling of Class A G-Protein-Coupled Receptors in the Age of the Structure Boom

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CryoEM reveals unprecedented binding site for Na_V1.7 inhibitors enabling rational design of potent hybrid inhibitors